Migraine Prophylaxis 2009

Dr Richard Peatfield. MD FRCP Princess Margaret Migraine ClinicCharing Cross HospitalLondon W6 8RF

r.peatfield@imperial.ac.uk

Prevalence of headache in the previous yearRasmussen et al J. Clin.Epidemiol. 44 1147 1991

Migraine Tension-type headache

Age group Men Women Men Womenn 387 353 387 353

25-34 5% 18% 68% 93%

35-44 7% 14% 63% 92%

45-54 6% 12% 70% 82%

55-64 7% 19% 49% 74%

All ages 6% 15% 63% 86%

Functional impact of migraine by self-reported physician diagnosis of migraine. Lipton et al Headache 41 638 2001

INDICATIONS FOR MIGRAINE PROPHYLAXIS

Two attacks monthly.Less frequent attacks proving intractable.

 

Note

Mild Headache Nausea Photophobia Disability

Cost benefit. Abolition of the first hour or so of each headache if successful.

Persistent symptoms after 2 hours, eg:-

Quality of life can be impaired despite ‘effective’ treatment.

Migraine prophylactic medication

1. -blockers: Propranolol, Atenolol2. 5-HT Blockers: Pizotifen, Methysergide3. Tricyclics 4. Anti-epileptics: Valproate, Topiramate5. Calcium channel blockers: Flunarizine

6. Metabolic enhancers: Riboflavin, Nicotinamide7. ACE Inhibitors: Lisinopril8. Also: NSAID’s, Magnesium, Feverfew

Amine Modulation

Channel Modulation

Others

Prophylactic Agents: Europe v USA

Source: IMS MIDAS; 2002 RXs; N2C Migraine Products + top products used for G43 diagnosis code (which includes off-label products).

North America G5 EUROPE(France, Germany, Italy, Spain, and UK)

6%

Total others (26)

!0%

Other

β-blockers7%

Verapamil8%

Amitriptyline17%

Valproate sodium

12%Topiramate

14%

Gabapentin4%

Propranolol22%

Total others (33)15%

Otherβ-blockers

9%

Flunarizine

15%

Amitriptyline10%

Valproic acid1%

propranolol33%

Pizotifen17%

Nortriptyline

Migraine - Preventive TreatmentFirst choice

• betablockers• antiepileptic drugs

Second choice• antidepressants• calcium-antagonists • serotonin antagonists

Third choice• riboflavin, coenzyme Q10, magnesium

“Special cases“• menstrual migraine: NSAIDs, continuous contraceptive

pill, naratriptan, frovatriptan

• exercise induced: betablockers, indomethacinSandor 2004

Daily dose (adult) mg.

Start Max.

Propranolol 80 320Atenolol 50 150Pizotifen 0.5 1.5Methysergide 1 6Valproate 400 1600Naproxen 250 1000Amitriptyline 10-25 100 

Conventional migraine prophylactic drugs

Blockers Diener

Mode of action unknown; no animal models No proper dose finding studies of propranolol

160=80mg, or 160>80? Short titration times, never over 12 weeks Metoprolol second greatest number of trials, again for a short time Bisoprolol largest, best designed trial 226 patients. All seem of equal efficacy ~ 50% response rate. No correlation between plasma levels and efficacy

16 comparative trials Metoprolol > aspirin Propranolol > Nifedipine

Neither trial with placeboFlunarizine = Propranolol [Cephalalgia 2001]

Blockers Diener

Propranolol since 1964; very cheap26 drugs now available:-

Effective Perhaps not

Propranolol AcebutololMetoprolol AlprenololTimolol OxprenololBisoprolol PindololNadololAtenolol

?? Differences due to trial design

http://www.cochrane.org/reviews/en/ab003225.htmlPropranolol

Antidepressants Bendtsen

Migraine Widely used – second only to -blockers.No DBXO trials following IHS guidelinesThree small trials of amitriptyline 1973-1987

21-42% reduction in attacksEffect independent of depressive state

Trials of fluoxetine- benefit modest if any

Tension-type headache Most trials of amitriptyline (1964-1996) show benefitPfaffenrath’s trial had a tough endpointBendtsen’s own trial:- (1996)

Amitriptyline effective; Citalopram had no effectHolroyd 2001 144 patients 30% reduction

Antidepressants

Discordant results with SSRI’s:-

Patients do not care any moreHeadache continues unaltered

Not evidence based!!

Valproate in Migraine Prevention: Efficacy—ITT

8

3842

36

0

5

10

15

20

25

30

35

40

45

Placebo 500 mg 1000 mg 1500 mg

*P<.05.ITT=intent to treat.

Klapper J and the Divalproex Sodium in Migraine Prophylaxis Study Group. Cephalalgia. 1997;17:103-108.

Mean Reductionin 4-WeekMigraine

Frequency(%)

Mean Reductionin 4-WeekMigraine

Frequency(%)

Valproate

* *

*

Valproate in Migraine Prevention: Overall Responder

Rate—ITT

*P≤.05 (vs placebo).ITT=intent to treat.

Klapper J and the Divalproex Sodium in Migraine Prophylaxis Study Group. Cephalalgia. 1997;17:103-108.

21

44

0

10

20

30

40

50

60

Placebo Valproate

≥50%

ResponderRate (%)

≥50%

ResponderRate (%)

*

Divalproex in Migraine. Cochrane reviews 2006

http://mrw.interscience.wiley.com/cochrane/clsysrev/articles/CD003226/frame.html

Methysergide

• 5HT2 A,B&C receptor antagonist(But mianserin, ketanserin and ICI 169369 do not work)

• Metabolised to Methylergometrine, an agonist at 5HT1 B

receptors.- Greater bioavailability- Longer half-life.

• Antagonist at 5HT7 receptors.

• Increases Neuropeptide Y levels in the hypothalamus – appetite stimulant

Methysergide in Migraine Prophylaxis

60 patients, double blind cross over.6 mg daily.

Placebo Methysergide

No attacks 4 16Over 50% fewer 12 18Unchanged 44 26

p<0.01

Petersen & Moller: Clin.Pharm.Ther. 1966 7 520.

Methysergide: side effects

Less severe than the publicity!

Pain in the legs (?vasospasm) is less likely if the drug dose is

increased slowly ( 0.5mg daily for a few days- etc etc).

Retroperitoneal and cardiac fibrosis.

Rare; commoner with larger doses.

In one series 11/19 affected patients had received > 8mg/day

Seen after 6mg/day or less.

Reversible if the drug is stopped.

The risk of retroperitoneal fibrosis is lessened if the

drug is stopped for 1 month every 6 months.

Worth regular auscultation, and checking a renal ultrasound and echocardiogram annually

Methysergide: fibrotic side effects

What to do in the ‘Holidays’? • Topiramate • Prednisolone ( 50mg, reducing by 5mg/day)

n cases

Continuous use ( ?Dose) 1000 36

Stopping for 1 month annually 300 Nil

(Bala Am Ht J 1974 88 640)

Topiramate in Migraine Prevention

Response to Topiramate Therapy(50% Responder Rate)

*P<.05; †P<.01; ‡P<.001.

Mathew N et al. Neurology. 2003;60(suppl 1):A336; Brandes JL. et al. JAMA. 2004;291(8):965-973

23 23

52‡54‡

36*

47‡49‡

39†

0

10

20

30

40

50

60

Placebo 50 mg/d 100 mg/d 200 mg/d

MIGR-001

MIGR-002

% of patients % of patients with with >>50% 50%

reduction in reduction in Migraine Migraine

FrequencyFrequency

% of patients % of patients with with >>50% 50%

reduction in reduction in Migraine Migraine

FrequencyFrequency

TopiramateTopiramateTopiramateTopiramate

MIGR-001 / MIGR-002

Topiramate in Migraine Prevention: Onset of Action

-2.5

-2.0

-1.5

-1.0

-0.5

0.00 1 2 3 4 5 6

Placebo (n=115) Topiramate 50 mg/d (n=117)

Topiramate 100 mg/d (n=125) Topiramate 200 mg/d (n=112)

*P=.032; †P≤.015; ‡P<.001.

††

†

†

†

†

*Cumulative Cumulative Reduction in Reduction in

Mean Mean Migraine Migraine

FrequencyFrequency

‡‡

‡‡

‡

‡

MonthMonth

Mathew N et al. Neurology. 2003;60(suppl 1):A336; Brandes JL. et al. JAMA. 2004;29198):965-973

Topiramate in Migraine. Cochrane reviews 2006

http://mrw.interscience.wiley.com/cochrane/clsysrev/articles/CD003226/frame.html

Topiramate side-effects 50% get paraesthesiae –

carbonic anhydrase inhibition - try K+

20% Cognitive – concentration, memory, speech unpredictable ? K+

1½% Kidney stones Calcium oxalate Fatigue Anorexia; weight loss Diarrhoea Taste change Glaucoma

Brandes JAMA 2004 291 965; Silberstein Arch N. 2004 61 490

‘Therapeutic gain’ compared to placebo proportion of patients with 50% reduction in attack frequency (verum – placebo)

1st choice (EBM)

well tolerated substances, mechanism: energy metabolism

new antiepileptics

42flunarizine

gabapentin 22

topiramate 40

0 5 10 15 20 25 30 35 40 45 50 55

20amitriptyline

40betablockers

45valproate

therapeutic gain

37riboflavin (Vit B2)

18Mg (24 mM)

33coenzyme Q10

[Sandor 2004]

Levetiracetam in Headache

Co-sponsored prospective multicentre trial of 1.5G- No benefit. Unpublished. ?? Suppressed (? Dose too low)

Young (Philadelphia) Open study 3G35% >50% reduction in attacksNo control seriesPersonality change problems

Headache 2004 44 2238Clin J Pain 2004 20 198All retrospective

Angiotensin :- Converting enzyme inhibitors and receptor antagonists

Lisinopril 20mg is an effective prophylactic20% improvement above placebo in a DBXO trial in 47 patients[Schrader BMJ 2001 322 19-22].

Fewer headaches in patients on ACE inhibitors[Etminan Am J Med 2002 112 642-6]

 

Candesartan Trial of 16mg daily in 57 migraine patients32-46% had headache reduced by 50%No significant adverse events[Tronvik. JAMA 2003 289 65-9].

Tronvik. JAMA 2003 289 65-9

Binding of 5-HT2B receptors

Botulinum ToxinZinc dependent Metalloproteinases

Cleaves proteins responsible for exocytosis of transmitter vesiclesActs on sensory afferents tooInhibits release of all neurotransmitters, including SP, CGRP etc, in doses comparable to those used in man.

Consensus is that is does work, so long as there are enough separateinjection sites – 15-20 per patient.Sites of action are not confined to the neuromuscular junction

In published trials most patients are unaware of the treatment used.Some trials are biased; placebo patients less severe.

Type A – Most potent and lasting effect

Light Chain cleaves SNAP 25 protein inside membrane - 1 of the 3 proteins in SNARE complex that leads to Ach release

Collateral axonal sprouts lead to early recovery, until original terminal recovers

Sensory effects of botulinum toxin

In cervical dystonia low doses relieve pain before the motor effectsRelja 2006

Suppresses secondary inflammatory pain after formalin injection Release of Substance P, CGRP, etc.Cui Pain 107 125 2004

Less c-fos expression in cervical neuronesGazer~~ Pain 122 315 2006

Botulinum Toxin in Chronic Daily Headache

Mathew Headache 45 293 2005. 355 subjects

47% met criteria for analgesic abuse; slightly more in the active group Side effects in 2.3% only (usually neck pain from weakness)

Primary end-point (change in the number of headache free days) not met --6.7 cf 5.2.in placebo non-responders Doubtful clinical significance

Significant improvement in:-Headache frequency The proportion with >50% decrease of headache days per monthThose not on prophylaxis [H 45 315 2005]

Botulinum Toxin

NO effect in tension-type headache

Possible effect in Migraine High Placebo response rates

Greatest potential role in ‘Chronic Migraine’

Blinding

Aesthetic changeLess Sweating

Incidental effect in cosmetic patients

In the trials the number of patients guessing correctly fell from 65% to 55% as they improved!

Exploding vs Imploding Headaches Burstein Kyoto, Dodick AAN 2006

Exploding Bursting 12% responded

Imploding Tightening 92% responded

Ocular 100% responded

? Related to fine extracranial c-fibres passing through the skull to innervate the dura (in the rat)

Differences in Migraine Features for Botulinum Toxin-A Responders and Nonresponders

92

8 11

89

0

10

20

30

40

50

60

70

80

90

100

Exploding Imploding

Responders Non-responders

Burstein et al., Neurology 2006

88

-2

71

0

52

2.5

-20

0

20

40

60

80

100

Frequency Duration Pain Severity

Responders Non-responders

% o

f st

udy

part

icip

ants

Description of Headache Pain

% im

prov

emen

t o

ver

pre-

trea

tmen

t ph

ase

Headache Characteristics

N=35 respondersN=24 nonresponders

Expensive!

£129 for a 100 unit ampoule4 patients at low dose – 25 units per patient

Trial used 150-190 units per patient

USA different from UK!

Chronic migraine sufferers are already costing insurers a lot of money by the time they are referred for Botox treatment, and the additional costs are seen as marginal and the potential gains large.

Vertical integration of costs and savings in the USA

Scans

Multiple Opinions

Analgesics

Emergency $600

If you don’t have Botox…

USA UK

Someone

Else’s

Budget! Cost Botox

of

Prophylaxis in real life

MIGRAINEPROPHYLACTIC MEDICATION

Dose used in trials Cost / 28 days Percent of patiens likely mg £ to make a 50% improve- ment compared to

placebo

  Propranolol 240 1.44 34

Atenolol 100 0.95 33

 Pizotifen 3 8.28 28

 Methysergide 6 37.68 30

 Valproate 1000 7.84 34

 Amitriptyline c100 2.41 32

Topiramate 100 32.07 31

Revised prices 27 November 2005

Consensus view on migraine prophylaxis

Offered :- Patients with 6 or more headache days per month; 4 or more days with some impairment; or 3 or more days with severe impairment.

Considered:- Patients with 4 or 5 headache days per month with normal functioning; 3 days with some impairment; or 2 days with severe impairment.

Not indicated:- Patients with <4 headache days per month with normal functioning; or no more than 1 day per

month regardless of impairment.

Lipton Neurology 2007 68 343

Principles of Preventative Pharmacotherapy Goadsby

Clarify Diagnosis:- History is taken, not given. Explain what it means to the patient. Assess the burden to the patient. Establish what the patient expects. Be clear what the Physician can offer; limited! Advise on areas where the patient can intervene. Optimise the treatment of acute attacks. Plan preventative treatment.

Migraine: Prophylactic trials  Small trials in single centres Some crossover and some parallel group designs Variety of endpoints used:-

- Percentage of patients improving in categories

- Overall percentage improvement Not a comprehensive metaanalysis:-

results from individual selected trials.

DRUGS ACTING ON SEROTONIN RECEPTORS(Adapted from Saxena)

 Sumatriptan Pizotifen Methysergide Ergotamine

 

5HTID Agonist Inactive Partial AgonistAgonist

5HT2A Inactive Antagonist Antagonist Agonist

5HT2C Inactive Antagonist Antagonist Agonist5HT3 Inactive Inactive Inactive Inactive

 

Select for positive side effects, e.g.

• anxiety → betablocker

• insomnia → sedating tricyclic at night (amitriptyline)

• constipation → magnesium

• obesity → topiramate

• comorbid depression → antidepressant in sufficient dosage

Sandor 2004

Long Q-T interval

Upper limit 450msec, less in women

Long QT interval

Measure from the beginning of Q to the end of TResting ECG can be normal –need an exercise testPatients may collapse during exercise

QTc is corrected for the heart rate

>460msec in women; 440msec in men

Congenital long Q-T interval

• 7 identified genes; 300 mutations

• Mostly related to K+ Channels

• Risk of sudden death,

especially during sudden arousal or exercise

• Prophylactic -blockers may lower this risk

Drugs prolonging the Q-T interval

Withdrawn Terfenadine, Astemazole, Cisapride.

Hazardous Amiodarone, Sotalol. Quinidine

Care! Erythromycin, Chlorpromazine,

Haloperidol, Tricyclics, Domperidone,

Amantadine.

www.longqt.org

Valproate in Migraine Prevention

• 16-week double-blind, placebo-controlled trial of valproate; N=171

• Study design

– 4-week placebo run-in

– Patients randomized to receive 500, 1000, or 1500 mg/d valproate or placebo for 12 weeks

• Initial dose, 250 mg/d

• Titration every 4 d (8 d for 500 mg/d group) of 250 mg/d to maintenance dose

• 8-week maintenance phase

– Efficacy evaluations every 4 weeks

Klapper J et al. Cephalagia. 1997;17:103-108.

Topiramate in Migraine Prevention

MIGR-001 / MIGR-002 / MIGR-003

19%24%

17% 17%

6%

6%

6% 6%

0

5

10

15

20

25

30

Topiramate100 mg/d

(MIGR-001)

Topiramate100 mg/d

(MIGR-002)

Topiramate100 mg/d

(MIGR-003)

Propranolol160 mg/d

(MIGR-003)

>95%

75%-94% Reduction

% of% ofPatients Patients

75% and 95% Responder Rate75% and 95% Responder Rate

Mathew N et al. Neurology. 2003;60(suppl 1):A336; Brandes JL et al. JAMA. 2004;291(8):965-973